Bone growth compositions and methods

ABSTRACT

The present invention provides an improved technique for spinal fusion involving the administration of an HMG-CoA reductase inhibitor to a fusion. The HMG-CoA reductase inhibitor is preferably delivered to the site by a carrier. More preferably, the HMG-CoA reductase inhibitor is delivered to the site by a non-compressible delivery vehicle. The invention is suitable for promoting non-anatomic or heterotopic bone growth between any bony surfaces where bone growth is desired but does not naturally occur.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.10/282,338, filed Oct. 28, 2002 now U.S. Pat. No. 7,041,309, whichclaims benefit of priority to Provisional Application No. 60/388,222,filed Jun. 13, 2002, and Provisional Application No. 60/394,791, filedJul. 10, 2002. These applications are hereby incorporated by referencein their entirety.

SUMMARY OF THE INVENTION

The present invention relates to growth of non-anatomic or heterotopicbone. In one embodiment, HMG-CoA reductase inhibitors are used tostimulate non-anatomic bone growth in spinal fusion surgery. Preferably,the HMG-CoA reductase inhibitors are administered directly to the siteof fusion. More preferably, the HMG-CoA reductase inhibitors areadministered via a carrier, such as an open cell matrix. The carrier canfurther comprise of other therapeutic agents such as antibiotics,painkillers, antioxidants, growth factors, and timed release agent.

In another embodiment, the present invention involves the use of HMG-CoAreductase inhibitor to promote bone growth and fusion between any twobones. Bone fusion is effective in treatment post-traumatic,degenerative and/or inflammatory arthritis conditions. In oneembodiment, the HMG-CoA reductase inhibitor is used in podiatricsurgery, such as to immobilize the metatarsals or the ankle joint.Furthermore, HMG-CoA reductase inhibitors can be utilized in facialplastic and reconstruction surgeries, such as to fix the maxillary andmandibular bones, increase cheekbone morphology, and cranial vaultfixation and remodeling (e.g., due to craniosynostosis).

The present invention further discloses instrumentations and implantsthat are coated or comprise of HMG-CoA reductase inhibitors which can beused for purposes of enhancing non-anatomic bone growth.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a superior view of a 2^(nd) lumbar vertebra;

FIG. 2 is a lateral view of the cervical or lumbar spine;

FIG. 3 is a posterior view of the 3^(rd) and 4^(th) lumbar vertebrae;

FIG. 4 is a dorsal view of a dorsolateral fusion after totallaminectomy;

FIG. 5 is a perspective view of a carrier for use with one embodiment ofthe present invention;

FIG. 6 is a perspective view of a carrier packed in place for spinalfusion in one embodiment of the present invention;

FIG. 7 is a perspective view of an implantation stick in accordance withone embodiment of the present invention;

FIG. 8 is a perspective view of posterior lumbar lateral fusionaccording to one embodiment of the present invention using a pluralityof implantation sticks;

FIG. 9 illustrates a control rat;

FIG. 10 illustrates a rat that was treated with an HMG-CoA reductaseinhibitor; and

FIG. 11 illustrates palpation score of rats receiving HMG-CoA reductaseinhibitor treatment and controls.

DETAILED DESCRIPTION OF THE INVENTION

The vertebrae are bones that make up the spinal column, which surroundsand protects the spinal cord. At each level in the spinal cord, there isa disc space in the front and paired facet joints in the back. Workingtogether, these structures define a motion segment and permit multipledegrees of motion. Nerves from the spinal cord exit the spinal columnbetween each vertebra. Intervertebral discs are soft tissues positionedbetween each vertebra. The discs act as cushions between the vertebraeby absorbing energy while the spinal column flexes, extends, and twists.

The disc allows for movements of the vertebrae and allows people bendand rotate their neck and back. The type and degree of motion variesbetween the different levels of the spine: cervical (neck), thoracic(chest) or lumbar (low back). The cervical spine permits movement in alldirections. The thoracic spine protects the heart and lungs and is morerigid than the cervical spine due to rib presence. The lumbar spinepermits primarily forward and backward bending movements, flexion andextension.

In spinal fusion, one or more vertebrae, vertebral segments orcombination thereof, are fused to prevent any motion there between.There are many potential reasons for spinal fusion. Exemplary reasonsinclude treatment of a fractured vertebra, correction of deformity,elimination of pain from painful motion, treatment of instability andtreatment of cervical disc herniations. Some spinal fractures, includingthose associated with spinal cord or nerve injury, generally, requirefusion as part of the surgical treatment. While not all spinal fracturesrequire surgery, some fractures, including those associated with spinalcord or nerve injury, generally require fusion as part of the surgicaltreatment. In spondylolisthesis, a hairline fracture allows vertebrae toslip forward on top of each other. This condition may be treated byfusion surgery. Spinal fusion may also be used to correct certain typesof spinal deformity such as scoliosis. Another condition treated withfusion surgery is actual or potential instability (or abnormal orexcessive motion between two or more vertebrae). Cervical discherniations requiring surgery often require fusion as well as removal ofthe herniated disc (discectomy). With this procedure, the disc isremoved through an incision in the front of the neck (anteriorly) and asmall piece of bone is inserted in place of the disc. Although discremoval is commonly combined with fusion in the neck, this is notgenerally the case in the lumbar spine. Further, spinal fusion may berequired for the treatment of a painful spinal condition without clearinstability.

There are numerous surgical approaches and methods for performing spinalfusion. Many of these approaches involve placement of a bone graftbetween the vertebrae to be fused. The spine may be approached and thegraft placed either from the back (posterior approach), from the front(anterior approach) or by a combination of both approaches. The type andlocation of the incision for access to the spinal region depends on thearea needing treatment. The lower spinal vertebrae are repaired throughan incision directly over the spine (posterior lumbar approach). Theupper spinal vertebrae are repaired through an incision in the back orside of the neck (cervical spine). The middle spinal vertebrae arerepaired through an incision made in the chest and abdomen (anteriorthoracic spine). The abnormal or injured vertebrae are repaired andstabilized with bone grafts, metal rods, other instrumentation, or acombination of the above.

The most common types of spinal fusion include posterolateral gutterfusion, posterior lumbar interbody fusion (PLIF), anterior lumbarinterbody fusion (ALIF), anterior/posterior spinal fusion, cervicalfusion, thoracic fusion, and interlaminar fusion.

Posterolateral gutter fusion involves placing bone graft in theposterolateral portion of the spine (a region just outside the spine).The surgical approach to this spinal fusion is from the back through amidline incision that is approximately three inches to six inches long.Typically, bone graft is obtained from the pelvis (the iliac crest) andthe harvested bone graft is laid out in the posterolateral portion ofthe spine. The back muscles that attach to the transverse processes areelevated to support the bone graft. The back muscles are replaced overthe bone graft to create tension to hold the bone graft in place. Aftersurgery, the body attempts to heal itself by growing bone. The growth ofbone by the body grows the harvested bone graft and adheres the graft tothe transverse processes. At this point, spinal fusion is achieved andmotion at that segment is stopped.

Posterior lumbar interbody fusion (PLIF) involves adding bone graft toan area of the spine to set up a biological response that causes bone togrow between the two vertebrae and stop the motion at that segment. PLIFachieves spinal fusion by inserting bone graft directly into the discspace. The spine is approached through an incision (typically three tosix inches long) in the midline of the back and the left and righterector spinae are stripped off the lamina on both sides and at multiplelevels. After the spine is approached, the lamina is removed(laminectomy) to allow visualization of the nerve roots. The facetjoints, which are directly over the nerve roots, are trimmed to makemore space for the nerve roots. The nerve roots are retracted to oneside and the disc space is cleaned of the disc material. A bone graft,or interbody cage with bone, or other instrumentation or implant, isinserted into the disc space and the bone grows from vertebral body tovertebral body.

Anterior lumbar interbody fusion (ALIF) is similar to the PLIF, exceptthat in ALIF the disc space is fused by approaching the spine throughthe abdomen instead of through the back. In the ALIF approach, anincision (typically three to five inches) is made on the left side ofthe abdomen and the abdominal muscles are retracted to the side. Theperitoneum can also be retracted to allow the surgeon access to thefront of the spine. Some ALIF procedures are done using a minilaparotomy(one small incision) or with an endoscope (a scope that allows thesurgery to be done through several one-inch incisions). Regardless ofthe specific procedure, the aorta and vena cava are moved aside, thedisc material is removed and bone graft, or bone graft and anteriorinterbody cages, other implant, or instrumentation, is inserted.

Anterior/posterior lumbar fusion involves performing a lumbar interbodyfusion and a posterolateral gutter fusion to fuse both the front andback of the spine. Fusing both the front and back provides a high degreeof stability for the spine and a large surface area for the bone fusionto occur. The disc may be approached either as an ALIF or as a PLIF, andthe back part of the spine is fused with a posterolateral gutter fusion.

The neck is the upper portion of the spine and is made up of the sevenupper vertebrae which are often referred to as the cervical spine.Numerous cervical spine disorders require surgery for relief of painfulsymptoms. One of the basic underlying factors associated with most spinedisorders is the dehydration of the disks. Herniated cervical disk is acommon neck pain diagnosis which results when the center of the nucleusbulges through the annulus and presses on a nerve, resulting in neck orarm pain, or weakness in the arm. Cervical fusion involves thestabilization of two or more vertebrae by locking them together. One canapproach the cervical spine through a small incision in the front of theneck, usually within a skin fold line under the chin. After retractingneck muscles, the affected intervertebral disk is removed. This iscalled decompression. After removal, a bone graft may be inserted intothe intervertebral region to fuse the upper and lower vertebraetogether.

In many embodiments, spinal fusion involves the use of an implant to anarea of the spine, usually between two vertebrae. An implant can be, forexample, a compressible carrier (e.g., absorbable carrier such open cellmatrix) or a non-compressible carrier (e.g., an instrumentation).Implants come in many shapes, sizes and materials. An implant caninclude membranes, films, plates, foam, mesh plates, screws, taps orother formed pieces to be implanted in the body. Implants can be used tosupport or attach tissue/bone, separate tissue/bone from othertissue/bone, serve as a time-release vehicle, etc. Implants can be madefrom a variety of compounds. An implant is preferably resorbable andcomposed of a polymer such as, polyglycolide, polylactides,polycaprolactones, polytrimethylenecarbonates, polyhydroxybutyrates,polyhydroxyvalerates, polydioxanones, polyorthoesters, polycarbonates,polytyrosinecarbonates, polyorthocarbonates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), poly(maleic anhydride),polypeptides, polydepsipeptides, polyvinylalcohol, polyesteramides,polyamides, polyanhydrides, polyurethanes, polyphosphazenes,polycyanoacrylates, polyfumarates, poly(amino acids), modifiedpolysaccharides (e.g., cellulose, starch, dextran, chitin, chitosan,etc.), modified proteins (e.g., collagen, casein, fibrin, etc.) andtheir copolymers, or combinations thereof. Other polymers includepolyglycolide, poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(L-lactide), poly(D,L-lactide),poly(L-lactide-co-D,L-lactide), polycaprolactone,poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone)polytrimethylenecarbonate, poly(L-lactide-co-trimethylenecarbonate),poly(D,L-lactide-co-trimethylen-ecarbonate), polydioxanone andcopolymers, and polymer blends thereof.

In a preferred embodiment, a compressible carrier is a matrix, such asan open cell matrix. Preferably an open cell matrix comprises ofcollagen fibers. More preferably, such collagen fibers are coated withresorbable apatite, such as hydroxyapatite.

Non-compressible carriers such as surgical instrumentations can be usedas an adjunct to obtain a solid fusion or provide stability. Surgicalinstrumentation can be fabricated from titanium and/or alloys oftitanium, stainless steel, ceramic materials or rigid polymericmaterials. Typical medical instrumentations include, for example, rods,hooks, braided cable, plates, screws, and threaded interbody cages.Instrumentation can decrease the likelihood of non-union by maintainingspinal stability while facilitating the process of fusion. For example,instrumentation can be used to bridge space created by the removal of aspinal element such as an intervertebral disc. Instrumentation can alsobe used to correct a deformity or as an internal splint to hold thevertebrae together while the bone grafts heal. In a preferredembodiment, an instrument is coated with synthetic apatites, orpreferably hydroxyapatite. Unfortunately, even with the use ofinstrumentation, non-union remains a common problem.

Regardless of whether instrumentation or implants are used, bone or bonesubstitutes are preferably used to prompt the vertebrae to fusetogether. Traditionally, the surgical technique includes a graftingprocedure utilizing autologous bone harvested from a separate site. In atypical procedure, bone chips from a patient's pelvic bone aretransplanted, or grafted, to the spinal vertebrae to help fusion therebetween. Alternatively, allograft, bone harvested from a bone bank orother source, may be used. Similarly, synthetic and xenograft derivedbone substitutes (calcium phosphate, hydroxylapatite, and/or otherceramic based bone substitutes) may be used.

To function as a suitable bone graft for spinal fusion, a graft musthave three characteristics. It must provide a source of primitiveosteoprogenitor cells that form osteoblasts and osteocytes(osteopromotion). The graft material must produce local growth factorsto stimulate bone growth and vascularity in the area (osteoinduction).Lastly, it must act as a scaffold to bone ingrowth (osteoconduction).

Although the use of autologous bone for spinal fusion is common,harvesting bone graft from a patient's body has many disadvantages.Among other things, graft harvesting prolongs surgical time, increasesblood loss, increases the risk of infection, and can be a source ofchronic pain. Significantly, use of autologous bone does not alwaysensure successful fusion, even when used in combination withinstrumentation. Inherent limitations in autogenous and allogeneic bonegrafting have led to exploration of other technology, for example, usingbone morphogenic protein (BMP) in spinal fusion. As an adjuvant toallograft or as a replacement for harvested autograft, BMP can improvespinal fusion.

Bone growth and differentiation factors can be obtained in a variety ofways for application directly to a surgical site, including extractionof the factors from animal or human bone matrix, production of a singlefactor by cellular hosts by using recombinant technology, and directdelivery to cells at the site of desired bone formation of the DNAencoding for the factor. In particular, bone morphogenic proteins(BMPs), have been found to have an ability to stimulate formation ofcartilage and bone in vivo.

BMPs have a multifaceted osteoinductive role, acting as chemotacticagents, growth factors and differentiation factors. As chemotacticfactors, they can initiate the recruitment of progenitor and stem cellstoward the area of bone injury. As growth factors, they can stimulateboth angiogenesis and proliferation of stem cells from surroundingmesenchymal tissues. As differentiation factors, they can promotematuration of stem cells into chondrocytes, osteoblasts and osteocytes.

More specifically, BMPs can repair, regenerate and promote the growthand differentiation of bone in various parts of the skeleton. Thus, BMPsare extremely beneficial to patients undergoing bone fusion and/oraugmentation procedures (e.g., spinal fusion) by eliminating the needfor bone transplantation or bone grafting. Furthermore, several studiesreveal that improved results of bone fusion and stability can beachieved using recombinant human BMP-2 in various carriers as comparedto autologous bone grafts. See Pilitsis, J. G., Neurosurg. Focus, (2000)13 (6).

There are some disadvantages to using BMPs for promotion of bone growth.As BMPs are expressed in a large variety of tissues, receptors for theBMPs have numerous temporal and spatial patterns throughout the body.This suggests that BMPs may have effects on many tissues in addition tobone and their usefulness as therapeutic agents, particularly whenadministered systemically, may be limited. There is also some concernregarding the local administration of BMPs to a surgical site, as it maybe difficult to control BMPs effect on the surrounding tissue. Theeffects of BMPs in spinal fusion sites are particularly concerning ashypergrowth at or near the spine may pinch nerves and result in not onlypain but also possibly paralysis. Consequently, it may not be desirableto apply BMP directly to a spinal fusion site.

The present invention relates generally to the administration of HMG-CoAreductase inhibitors (statins), or prodrugs thereof or apharmaceutically acceptable salt of such statins or prodrug thereof topromote non-anatomical, or heterotopic, bone growth.

The terms “non-anatomic” and “heterotopic” bone growths refer to thegeneration of bone in regions that naturally do not grow bone.

The term “HMG-CoA reductase inhibitors” or “statins” as used hereinrefers to compounds that inhibit the enzyme 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the principalrate-limiting enzyme involved in cellular cholesterol biosynthesis. Thepathway is also responsible for the production of dolichol, ubiquinones,isopentenyl adenine and famesol. HMG-CoA reductase converts3-hydroxy-3-methyld-glutaryl CoA (HMG-CoA) to mevalonate.

HMG-CoA reductase inhibitors, or statins, enhance the production ofosteoblasts, the cells that produce new bone and enhance osteoblastdifferentiation. See S. E. Harris, et al., (1995) Mol. Cell. Differ. 3,137; see also G. Mundy, et al., Science, (1999) 286, 1946. Inparticular, statins have been known to promote BMP productionsystematically or in fracture sites. See U.S. Pat. Nos. 6,080,779,6,376,476, and 6,022,887.

Examples of the HMG-CoA reductase inhibitors of the present inventioninclude, but not limited to, lovastatin, pravastatin, velostatin,simvastatin, fluvastatin, cerivastatin, mevastatin, dalvastatin,fluindostatin, atorvastatin, or a prodrug thereof, a pharmaceuticallyacceptable salt of any such HMG-CoA reductase inhibitors, or prodrugthereof. Preferable salts include calcium and/or phosphate salts. In apreferred embodiment, the HMG-CoA reductase inhibitor is simvastatin orsimvastatin calcium. In another preferred embodiment, the HMG-CoAreductase inhibitor is lovastatin or lovastain calcium.

HMG-CoA reductase inhibitors may be readily prepared by processes knownin the chemical arts. Mevastatin, lovastatin, pravastatin, velostatin,simvastatin, fluvastatin, cerivastatin and mevastatin, dalvastatin andfluindostatin can be made in accordance with the process set forth inU.S. Pat. Nos. 3,983,140, 4,231,938, 4,346,227, 4,448,784, 4,450,171,4,739,073, 5,177,080, 5,177,080, European Patent Application No. 738,510A2 and European Patent Application No. 363,934 A1, respectively, whichare all incorporated herein by reference in their entirety. Furthermore,atorvastatin can be prepared as described in U.S. Pat. No. 4,681,893,which is incorporated in its entirety by reference. The hemicalcium saltof atorvastatin, also known as Lipitor™, can be prepared as described inU.S. Pat. No. 5,273,995, which is incorporated in its entirety byreference. Other pharmaceutically-acceptable cationic salts ofatorvastatin may be readily prepared by reacting the free acid form ofatorvastatin with an appropriate base, usually one equivalent, in aco-solvent.

The present invention involves the use of such compounds to promotenon-anatomic bone growth, or bone growth in a site that does notnormally grow bone (e.g., aid in the fusion of two or more bone surfacesor augment growth of a bone surface). Bone fusion is effective intreatment of, for example, post-traumatic, degenerative and inflammatoryarthritis conditions.

In one embodiment, HMG-CoA reductase inhibitors are used to stimulatenon-anatomic bone growth at, near, surrounding or between any vertebraor vertebra structures including, but not limited to, the pedicles,dorsal spinal elements, traverse processes, accessory processes andsuperior articular processes, mamillary processes, laminae, vertebralbodies or combination thereof.

In another embodiment, HMG-CoA reductase inhibitors are used to enhancenon-anatomic bone growth at, near, surrounding or between bones of thefeet, including but not limited to, the tarsals, metatarsals, phalanges,tibia, fibula, calcaneous, talus, etc., or a combination thereof.

In a further example, the present invention envisions the administrationof HMG-CoA reductase inhibitors to a site at, near, surrounding orbetween facial bones, including but not limited to, the mandible,maxilla, lacrimal, vomer, frontal bone, nasal bone, palantine, inferiorconcha, hyoid, zygoma, or any combination thereof.

Administration of the HMG-CoA reductase inhibitor can be via any mode,which delivers the HMG-CoA reductase inhibitor locally to the site ofbone fusion or non-anatomic bone growth is desired. In preferredembodiments, the HMG-CoA reductase inhibitor is administered directly toa given site. Direct administration can be made in surgery when thewound is open or using an injection or other means to reach a desiredsite without surgery.

Preparation for direct application can comprise of aerosol sprays,solutions, lotions, gels ointments, preferably in pharmaceuticallyacceptable vehicle. Such vehicles include aliphatic alcohols,polyglycols, glycerol, polyethylene, glycol, esters of fatty acids, oils(e.g., arachis oil), bone-wax, polymeric bone cements, bone sealants,and silicones.

Alternatively, local application can be achieved by applying thecompounds herein into or onto a suitable carrier or diluent, orincorporating it into solid or semi-solid implants (non-compressiblecarriers) that are conventionally used in orthopedic surgery, such as,for example, dacron-mesh, gel-foam and kiel bone, or prostheses. In apreferred embodiment, the HMG-CoA reductase inhibitor is administered incombination with a compressible carrier such as a porous, open cellmatrix formed from collagen fibers coated with resorbablehydroxyapatite.

In any of the embodiments herein, a time-release formulations of HMG-CoAreductase inhibitor may be used. A time-release formulation preferablycomprises of hydrogel. A time-release formulation can be designed forshort term or long term release. A short term time-release formulationcan be designed to release a total of 0.1–1 g of HMG-CoA reductaseinhibitor per day, or more preferably 0.2–0.8 g of HMG-CoA reductaseinhibitor per day, or more preferably 0.3–0.6 g of HMG-CoA reductaseinhibitor per day, or more preferably 0.4–0.5 g of HMG-CoA reductaseinhibitor per day. Short term release formulations can last a few daysor a week.

A long term time-release formulation can be designed to release HMG-CoAinhibitor for a week or longer. In a preferred embodiment, a formulationfor long term time-release can be designed to release a total of0.01–0.5 g of HMG-CoA reductase inhibitor per day, or more preferably0.05–0.4 g of HMG-CoA reductase inhibitor per day, or more preferably0.07–0.3 g of HMG-CoA reductase inhibitor per day, or more preferably0.07–0.2 g of HMG-CoA reductase inhibitor per day.

In any of the embodiments herein, a preparation, vehicle, implant orcarrier may further support other compounds such as, for example,antioxidants, growth factors, antibiotics, anti-inflammatories,immunosuppressors, preservative, pain medication, other therapeutics,and excipient agents.

Examples of growth factors that may be administered in addition to theHMG-CoA reductase inhibitor include, but are not limited to, epidermalgrowth factor (EGF), transforming growth factor-alpha (TGF-.alpha.),transforming growth factor-beta (TGF-.beta.), human endothelial cellgrowth factor (ECGF), granulocyte macrophage colony stimulating factor(GM-CSF), bone morphogenetic protein (BMP), nerve growth factor (NGF),vascular endothelial growth factor (VEGF), fibroblast growth factor(FGF), insulin-like growth factor (IGF), cartilage derived morphogeneticprotein (CDMP), platelet derived growth factor (PDGF), or anycombinations thereof. Examples of antibiotics include antimicrobials andantibacterials.

The HMG-CoA reductase inhibitor may also be provided in a time-releasedrug delivery system, for example via a hydrogel, polymer membrane, orcoating. Methods of delivering the compounds using a time-release systeminclude those described in PCT publication WO 93/20859, incorporatedherein by reference. In other embodiments, the HMG-CoA reductaseinhibitor is administered percutaneously within a supporting compound atthe site where bone fusion is desired. Such embodiment promotes BMPproduction without necessitating surgery.

In one example, a procedure involves exposing the lamina and transverseprocesses, decorticating bone, and placing the carrier with HMG-CoAreductase inhibitor in the exposed area. Furthermore, the carrier mayemploy covalent or divalent bonding to the HMG-CoA reductase inhibitor.The carrier may also be used in conjunction or as a spinal fusion devicesuch as a cage.

The amount of HMG CoA reductase inhibitor administered depends on theprocedure, type of HMG CoA reductase inhibitor used, severity of thecondition, age of patient, and/or cardiac health of the patient. In oneembodiment, 0.1 to 1 grams of HMG-CoA reductase inhibitor areadministered per site per treatment. More preferably, 0.2 to 0.5 gramsof HMG-CoA reductase inhibitor is administered per site per treatment.More preferably, 0.25 to 0.3 grams of HMG-CoA reductase inhibitor areadministered per site per treatment. Treatment may be repeated severaltimes (e.g., twice, thrice, four times) or routinely (e.g., daily,weekly, monthly) as determined for example by X-ray or other indicationinto a given site.

The amount and timing of compounds administered to a patient will, ofcourse, be dependent on the subject being treated, on the severity ofthe affliction, on the manner of administration and on the judgment ofthe prescribing physician. Thus, because of patient-to-patientvariability, the dosages given herein are a guideline and the physicianmay titrate doses of the compound to achieve the treatment (e.g., bonemass augmentation) that the physician considers appropriate for thepatient. In considering the degree of treatment desired, the physicianmust balance a variety of factors such as bone mass starting level, ageof the patient, presence of preexisting disease, as well as presence ofother diseases (e.g., cardiovascular disease).

Methods of preparing various pharmaceutical compositions using carrierswith a certain amount of active ingredients are known, or will beapparent in light of this disclosure, to those skilled in the art. Forexamples of methods of preparing pharmaceutical compositions, seeRemington: The Science and Practice of Pharmacy, Mack PublishingCompany, Easton, Pa., 19th Edition (1995).

The present invention can be used during surgery or revision surgery. Acommon problem in spine fusion is that it is non-successful and resultsin non-union. Non-union is particularly difficult to treat andadministering an HMG-CoA reductase inhibitor during revision surgery canincrease the likelihood of fusion. Furthermore, the method andinstrumentations herein may be used for both open and minimally invasivesurgical procedures including endoscopic and arthroscopic procedureswherein access to the surgical site is achieved through a cannula orsmall incision.

Aside from spinal fusion, other procedures, for example, in podiatry,dentistry and facial reconstruction, which currently rely on wires,plates and screws may also benefit from the growth of non-anatomic bone.These procedures include arthrodesis for failed ankle arthoplasty and/orfor the first metatarsophalangeal joint (see Jones, S. et al., The Foot,(1999) 9, 142–144; see also Fadel, G. E., The Foot (2002) 12, 88–96);subtalar fusion surgery for patients who failed closed or open treatmentof a displaced intra-articular calcaneal fracture (see Csizy, M., J.Ortopaedic Trauma, (2003) 17(2), 106–112); fixation of bimaxillaryosteotomized segments (see Edwards, R., J. Oral Marillofac. Surg. (2001)59:271–276); and cranial vault remodeling (see Fearon, J A, Plastic andReconstructive Surgery, (2003) 111(1), 27–38).

It should be noted that while most contemplated applications of thepresent invention are concerned with use in humans, the products andmethods herein can be used in non-human animals as well.

FIG. 1 illustrates a 2^(nd) lumbar vertebra as an example vertebra fusedusing the present invention. The vertebra comprises a vertebral body 10with first and second pedicles 12 and 14 extending posteriorlytherefrom. The pedicles 12 and 14 are strong, cylindrical, anatomicbridges between the dorsal spinal elements and the vertebral body 10.The dorsal spinal elements comprise generally symmetrical transverseprocesses 16 and 18, accessory processes 20 and 22, superior articularprocesses 24 and 26, mamillary processes 28 and 30, and laminae 32 and34 which eventually meet at a single spinous process 36.

FIG. 2 depicts a lateral view of the cervical or lumbar spine. Top andbottom vertebral bodies 40 and 42 are separated by an intervertebraldisc 44. In spinal fusion, bone growth by the top and bottom vertebra ispromoted in order to cause the top and bottom vertebra to fuse. Thefusion typically involves placement of a bone graft, cage,instrumentation, or other implant, at a site where fusion is desired.The body engages in a natural bone growth healing process. The bonegrowth results in growth of the bone graft such that the top and bottomvertebrae are fused and motion therebetween is prevented. The bonegrowth may be between the vertebral bodies, through the intervertebraldisc space, between the transverse processes, between the laminae, orbetween a combination thereof.

In accordance with the present invention, an HMG-CoA reductase inhibitoris placed adjacent to the vertebrae as desired. This may be, forexample, adjacent to the transverse process, in the intervertebral discspace, or overlying the lamina. A preferred embodiment involvesadministering approximately 0.1–1 g, or more preferably 0.2–0.5 g, ofthe HMG-CoA reductase inhibitor, for example, lovastatin to a site pertreatment. Local administration of the HMG-CoA reductase inhibitor ispreferred and maybe performed by conventional methods such as injectionat the spinal fusion site, topical application to the site, or timerelease administration.

FIG. 3 shows a posterior view of the third and fourth lumbar vertebrae.From this perspective, the transverse processes 16 and 18 are moreclear. In spinal fusion surgery, the vertebrae may be joined at thetransverse processes 16 and 18 of adjacent vertebrae. One possibleprocedure in accordance with the present invention involves exposing thelamina 32 and 34 and transverse processes 16 and 18, decorticating thebone, and placing a carrier with HMG-CoA reductase inhibitor in theexposed area.

Preferably, local administration is performed by applying the HMG-CoAreductase inhibitor to a carrier and placing the carrier at the spinalfusion site. FIG. 4 depicts a dorsolateral fusion after totallaminectomy. The fusion bed involves the dorsal aspect of the transverseprocess, the facet joint, and the pars interarticularis. In oneembodiment of the current invention, an HMG-CoA reductase inhibitor isapplied to the carrier and the carrier is placed along the decorticatedtransverse processes. Antibiotics, other drugs, or pain medications maybe supported by the carrier. The HMG-CoA reductase inhibitor may also beprovided in a time release drug delivery system, for example via ahydrogel, polymer membrane, or coating.

In a preferred embodiment, the HMG-CoA reductase inhibitor isadministered to the site via a carrier, for example, a porous, open cellmatrix formed from collagen fibers coated with resorbablehydroxyapatite. FIG. 5 illustrates a suitable carrier 50. The carrier 50may comprise a collagen or cellular matrix. Further, the carrier 50 mayemploy covalent or divalent bonding to the HMG-CoA reductase inhibitor.The carrier 50 may also be used in conjunction with or as a spinalfusion device such as a cage.

As seen in FIG. 6, the carrier 50 may be packed with HMG-CoA reductaseinhibitor 52 and placed in the intervertebral disc space to promotefusion of the vertebra through that space. The HMG-CoA reductaseinhibitor is carried to the site by the carrier. Most preferably, theHMG-CoA reductase inhibitor 52 is delivered to the site in conjunctionwith spinal surgery instrumentation. In a preferred embodiment, theHMG-CoA reductase inhibitor fills the pores of a porous spinal surgeryinstrumentation device. Thus, the carrier is essentially soaked withHMG-CoA reductase inhibitor that enables a high volume of the HMG-CoAreductase inhibitor to be released. The carrier may further be coatedwith a time-release film.

A further embodiment of the invention includes delivering the HMG-CoAreductase inhibitor to the spinal fusion site with a noncompressibledelivery vehicle. The noncompressible delivery vehicle enables a largervolume of bone formation and therefore increases load-bearing capacityof the fusion site. FIG. 7 illustrates a non-compressible deliveryvehicle in the form of an implantation stick 60. The stick 60 can behollow or porous and includes a plurality of openings 62. Theimplantation stick 60 may be packed with an HMG-CoA reductase inhibitorin a time-release manner, or with hydroxy appetite.

FIG. 8 illustrates posterior lumbar lateral fusion according to oneembodiment of the present invention using a plurality of implantationsticks 60. In accordance with the present invention, the lamina andtransverse process are exposed, bone decorticated, and the carrier withHMG-CoA reductase inhibitor is placed in the exposed area. In theembodiment of FIG. 8, the carrier comprises a plurality of implantationsticks 60 that are placed approximately on the adjacent decorticatedlamina and transverse processes bridging the gap between the transverseprocess of an upper vertebra 40 and the transverse process of a lowervertebra 42. The noncompressible delivery vehicle, for example, theimplantation sticks 60, retains a volume between the vertebrae for bonegrowth. The non-compressible delivery vehicle is packed with an HMG-CoAreductase inhibitor to promote bone growth along the vehicle.

The present invention may involve any suitable instrumentation. Forexample, a screw may be employed, the screw having an HMG-CoA reductaseinhibitor carried thereupon. The screw may comprise a porous material,the HMG-CoA reductase inhibitor being soaked in the pores. Alternately,the screw may be cannulated with the HMG-CoA reductase inhibitor beingprovided in the hollow opening. Such screws maybe used in odontoid screwfixation or c1–c2 transarticular screw fixations. The screw may traversethe fracture site or the joint to produce fusion at the level of thejoint.

While various embodiments in accordance with the present invention havebeen shown and described, it is understood that the invention is notlimited thereto, and is susceptible to numerous changes andmodifications as known to those skilled in the art. Therefore, thisinvention is not limited to the details shown and described herein, andincludes all such changes and modifications as encompassed by the scopeof the appended claims.

EXAMPLES Example 1

Twelve male Sprague Dawley rats, each weighing approximately 500 gramswere selected. Each rat underwent anesthesia with Nembutal (50 mg/kgi.p.). Incision over two regions, the thoracic and lumbar, of the spinein each animal were made. Each incision allowed for the exposure ofspinous processes and lamina of at east 2 levels per region.Decortication was carried out at each thoracic and lumbar region using ahigh-speed drill. Over the decorticated levels, nothing, gelmatrix,gelmatrix plus 8 mg lovastatin or gelmatrix plus 16 mg lovastatin wereadded. 8 mg I.M. of antibiotic Cefazolin™ was subcutaneouslyadministered to each rat.

For the purposes of analysis, the rats were divided into three groups.Group A consisting of rats 1–4 was treated with nothing or gelmatrix.Group B consisting of rats 5–8 was treated with gelmatrix and 8 mg oflovastatin. And, group C consisting of rats 9–12 was treated withgelmatrix and 16 mg of lovastatin. The following is a summary of thedata:

TABLE 1 Spinal Rat wt (g) Region Treatment 1 475 T Nothing L Gel 2 536 TGel L Nothing 3 633 T Nothing L Gel 4 499 T Gel L Nothing 5 542 T Gel LGel + 8 mg 6 480 T Gel + 8 mg L Gel 7 504 T Gel L Gel + 8 mg 8 477 TGel + 8 mg L Gel 9 483 T Gel L Gel + 16 mg 10 415 T Gel + 16 mg L Gel 11440 T Gel L Gel + 16 mg 12 459 T Gel + 16 mg L Gel

After en bloc removal, two observers manually palpated the spine of eachrat in a blinded fashion. Palpation was made by flexion and extension atthe level of the arthrodesis and at the adjacent levels proximally anddistally. This method of evaluation has previously been shown to be moreaccurate than plain radiographs and to correlate closely withbiomechanical test data. Each motion segment was graded on a qualitativescale (0–3) based on the strength of the fusion. A solid fusion havingno motion was given a score of 3. A score of 1 or 2 was given tosegments that had more restricted motion than the negative control. Nofusion was scored as a 0. A summary of the palpitation scores given toeach group of rats is illustrated in FIG. 11.

Results indicated that seventy five percent of the rats treated withlovastatin had a stronger fusion at the treated region than rats nottreated. Furthermore, the fusion grades given to treated rats appearedto be dose dependent.

Example 2

Spines of rats treated and untreated with HMG-CoA reductase inhibitorwere fixed and processed for pathology analysis by light microscopy andradiographic analysis. The X-ray of the spine of a rat that was nottreated with HMG-CoA reductase inhibitor is illustrated in FIG. 9. Ratstreated with HMG-CoA reductase inhibitor appear to have an augmentedspinal fusion in a dose dependent manner as is illustrated in FIG. 10.

1. A method for enhancing non-anatomic bone formation in a site, the method comprising the steps of administering an HMG-CoA reductase inhibitor to the site.
 2. The method of claim 1 wherein the HMG-CoA reductase inhibitor is lovastatin, or any salt, prodrug or derivative thereof.
 3. The method of claim 1, wherein the HMG-CoA reductase inhibitor is pravastatin, or any salt, prodrug or derivative thereof.
 4. The method of claim 1 wherein the HMG-CoA reductase inhibitor is simvastatin, or any salt, prodrug or derivative thereof.
 5. The method of claim 1 wherein the HMG-CoA reductase inhibitor is atorvastatin, or any salt, prodrug or derivative thereof.
 6. The method of claim 1 wherein the HMG-CoA reductase inhibitor is dalvastatin, or any salt, prodrug or derivative thereof.
 7. The method of claim 1 wherein the HMG-CoA reductase inhibitor is fluindostatin, or any salt, prodrug or derivative thereof.
 8. The method of claim 1 wherein the HMG-CoA reductase inhibitor is cerivastatin, or any salt, prodrug or derivative thereof.
 9. The method of claim 1 wherein the HMG-CoA reductase inhibitor is mevastatin, or any salt, prodrug or derivative thereof.
 10. The method of claim 1 wherein the HMG-CoA reductase inhibitor is velostatin, or any salt, prodrug or derivative thereof.
 11. The method of claim 1 wherein the HMG-CoA reductase inhibitor is administered using a carrier.
 12. The method of claim 11 wherein the carrier is a non-compressible carrier.
 13. The method of claim 11, wherein the non-compressible carrier is coated with the HMG-CoA reductase inhibitor.
 14. The method of claim 11 wherein the carrier is a compressible carrier.
 15. The method of claim 14 wherein the compressible carrier is a hydrogel.
 16. The method of claim 11 wherein the carrier is an open cell matrix.
 17. The method of claim 16 wherein the open cell matrix is formed from collagen fibers.
 18. The method of claim 17 wherein the collagen fibers are coated with resorbable hydroxyapatite.
 19. The method of claim 18 wherein the hydroxyapatite further comprises calcium.
 20. The method of claim 11 wherein the carrier further comprises another compound.
 21. The method of claim 20 wherein the compound is an antibiotic.
 22. The method of claim 20 wherein the compound is a pain medication.
 23. The method of claim 20 wherein the compound is an antioxidant.
 24. The method of claim 12 wherein the non-compressible delivery vehicle comprises at least one implantation stick for application to the site such that the implantation stick extends lengthwise between the upper and lower vertebrae.
 25. The method of claim 1 wherein the step of administering the HMG-CoA reductase inhibitor includes the step of applying the HMG-CoA reductase inhibitor with a time release drug delivery system.
 26. The method of claim 25 wherein the time release drug delivery system comprises a hydrogel.
 27. The method of claim 1 wherein the step of administering the HMG-CoA reductase inhibitor includes administering 0.1–1 gram of the HMG-CoA reductase inhibitor to the site per treatment.
 28. The method of claim 27 wherein treatment is repeated 3–5 times.
 29. A method for promoting spinal fusion, the method comprising the steps of: exposing an upper vertebra and a lower vertebra; identifying a site for fusion between the upper and the lower vertebra; exposing a bony surface on each of the upper and the lower vertebra at the site for fusion; applying an HMG-CoA reductase inhibitor to a carrier; applying the carrier to one of the exposed bony surfaces at the site.
 30. The method of claim 29 wherein the spinal fusion is selected from the group consisting of a posterolateral gutter fusion, a posterior lumbar interbody fusion, an anterior lumbar interbody fusion, an anterior/posterior spinal fusion, a cervical fusion, a thoracic fusion and an interlaminar fusion.
 31. The method of claim 30 wherein the spinal fusion is the posterolateral gutter fusion.
 32. The method of claim 31 wherein the HMG-CoA reductase inhibitor is place in a posterolateral portion of a spine on a first and a second transverse processes.
 33. The method of claim 30 wherein the spinal fusion is the posterior lumbar interbody fusion.
 34. The method of claim 31 wherein the HMG-CoA reductase inhibitor is administered directly into a disc space.
 35. The method of claim 30 wherein the spinal fusion is the anterior lumbar interbody fusion.
 36. The method of claim 35 wherein the HMG-CoA reductase inhibitor is administered directly into a disc space.
 37. The method of claim 30 wherein the spinal fusion is the anterior/posterior spinal fusion.
 38. The method of claim 30 wherein the spinal fusion is the cervical fusion.
 39. The method of claim 30 wherein the spinal fusion is the thoracic fusion or interlaminar fusion.
 40. The method of claim 29 wherein the carrier is a non-compressible delivery vehicle.
 41. The method of claim 30 wherein the non-compressible delivery vehicle comprises of at least one implantation stick for application to the site such that the implantation stick extends lengthwise between the upper and lower vertebrae.
 42. A method of promoting non-anatomical bone growth between two bony surfaces, the method comprising the steps of: identifying a site between two bony surfaces where bone growth is desired but does not naturally occur; exposing bone at each of the two bony surfaces; applying an HMG-CoA reductase inhibitor to at least one of the bony surfaces.
 43. The method of claim 42 wherein the step of administering the HMG-CoA reductase inhibitor further includes the steps of providing the HMG-CoA reductase inhibitor on a carrier and applying the carrier to the site.
 44. The method of claim 43 wherein the carrier is a non-compressible delivery vehicle.
 45. The method of claim 44 wherein the non-compressible delivery vehicle comprises of steel, ceramic, titanium, coral or hydroxyapatite.
 46. A method for fixation of maxillary and mandibular osteotomies comprising: identifying a site for fusion between a maxillary bone and a mandibular bone; exposing a bony surface at each of the two bones; applying an HMG-CoA reductase inhibitor to at least one of the bony surfaces.
 47. The method of claim 46 wherein the HMG-CoA reductase inhibitor is on or in a carrier.
 48. The method of claim 47 wherein the carrier is a non-compressible implant.
 49. The method of claim 47 wherein the carrier is an open cell matrix.
 50. The method of claim 49 wherein the matrix is composed of collagen.
 51. The method of claim 47 wherein the carrier is a timed release carrier.
 52. A carrier for enhancing bone formation wherein said carrier comprises an HMG-CoA reductase inhibitor.
 53. The carrier of claim 52 further wherein said carrier is an open cell matrix.
 54. The carrier of claim 53 wherein the matrix is formed of collagen.
 55. The carrier of claim 52 wherein the carrier further comprises an antibiotic, a pain medication, a growth hormone or a combination thereof.
 56. The carrier of claim 52 wherein said carrier is non-compressible.
 57. The carrier of claim 56 wherein the carrier comprises of steel, ceramic, titanium, coral or hydroxyapatite. 